As the primary etiological agent for the dental caries development, Streptococcus mutans has developed multiple mechanisms to colonize the tooth surface and become an integral part of the dental biofilm. Under unhealthy conditions, pathogenic bacteria, namely acidogenic and aciduric species, begin to dominate the oral population while the number of beneficial organisms such as Streptococcus sanguinis and Streptococcus gordonii decrease significantly. Biofilm then ferments the dietary carbohydrates producing acid byproducts such as lactic acid which causes a decrease on oral pH leading to the demineralization of tooth. Normally, the salivary system employs buffer systems to maintain a healthy pH of 6.0?7.5 in the oral cavity. A drop in the pH below 5.5 is potentially harmful to the hard (enamel and dentin) and soft tissues in oral cavity. Therefore, we hypothesize that a biofilm inhibitor that does not affect the viability of oral commensal bacteria delivered in to oral cavity in a pH responsive (released when the pH drops below 5.5) manner will be an ideal approach to prevent/treat dental caries. Preliminary studies from our labs have identified such specific low micromolar small-molecule biofilm inhibitors that do not affect the growth of oral commensals. We have established that these compounds produce their biofilm inhibition by inhibiting S. mutans virulence factor, glucosyl transferases. Two active compounds identified from these studies, SN204 and SN199 consistently showed dose dependent inhibition of biofilms with IC50 values of 16.7 M and 15 M, respectively. Furthermore these compounds did not inhibit the viability of S. mutans and of the other two commensal species (S. sanguinis and S. gordonii) up to 200 M, which is a much higher concentration than their biofilm IC50 values. A 43 day treatment of S. mutans (UA159) infected dental caries in gnotobiotic rats with SN204 or SN199 have resulted in considerable reduction in buccal, sulcal and proximal caries scores compared to the control groups. Given that the salivary pH less than 5.5 is potentially harmful to the enamel, we aim to encapsulate our lead biofilm inhibitors within the network of poly(methacrylic acid) (PMAA) hydrogel nanoparticles which possess pH sensitivity and explore the effect of such hydrogel encapsulated biofilm inhibitors (HEBIs) on biofilm formation and caries development. In the preliminary studies, SN199 has been successfully encapsulated into hydrogel with a loading capacity of 1.7210-5 ng per particle. As proof of principle, we have demonstrated the pH dependent drug release of the small-molecule anticancer drug, doxorubicin from PMAA hydrogel in the previously reported studies. The overall goal of this proposal is to demonstrate the biofilm inhibitory activity of HEBIs in vitro & in vivo and establish its potential as a novel and selective biomaterial that can be used for the prevention and treatment of dental caries. The long term goal of this project is to develop these HEBIs as dental strips/creams that can be used any time, especially at night when sleeping in order to provide a steady, on-demand release of biofilm inhibitors in the oral cavity to prevent/treat dental caries.